HCC, non-microsatellite instability-high (MSI-H)/ deficient mismatch repair (dMMR) CRC, PDAC, and BTC MedDRA version: 21.1 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 100000004864
Conditions
Sponsors
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Has histopathologically or cytopathologically documented, advanced solid tumor as follows: Cohort A HCC Cohort B CRC (non-MSI-H/dMMR) Cohort C PDAC Cohort D BTC (includes intrahepatic, extrahepatic CCA and gall bladder cancer) 2. Participant must have progressed on or since the most recent treatment 3. Has measurable disease per RECIST v1.1 as assessed locally and verified by BICR 4. Submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated 5. Participants must fulfill cohort-specific requirements including prior line of therapies 6. Is male or female, at least 18 years of age, at the time of signing the informed consent 7. Male participant is eligible to participate if he agrees to the following during the intervention period with belzutifan or lenvatinib and for at least 7 days after last dose of study intervention with belzutifan or lenvatinib: •Be abstinent from heterosexual intercourse OR • Must agree to use contraception unless confirmed to be azoospermic 8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Is not a WOCBP OR • Is a WOCBP and using a contraceptive method that is highly effective 9. The participant (or legally acceptable representative if applicable) has provided documented informed consent for the study 10. Has ECOG performance status of 0 to 1 within 7 days of before the start of study intervention 11. Has adequate organ function 12. Has adequately controlled BP with or without antihypertensive medications, defined as BP =150/90 mm Hg with no change in antihypertensive medications within 1 week before start of study treatments. Cohort A 13. Has a diagnosis of HCC confirmed by histology, or cytology 14. Have BCLC Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach 15. Have a Child-Pugh class A liver score within 7 days before first dose of study intervention 16. Participants with past or ongoing HCV infection will be eligible for the study. The treated participants must have completed their treatment at least 1 month before starting study intervention 17. Participants with controlled HBV will be eligible as long as they meet the following criteria: •Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 500 IU/mL before first dose of study intervention. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study treatment •Participants who are positive for anti-HBc, negative for HbsAg, and negative or positive for anti-HBs, and who have an HBV viral load under 100 IU/mL, do not require HBV antiviral prophylaxis 18. Has not received any systemic chemotherapy, including anti-VEGF therapy, anti-PD- 1/PD-L1 or any systemic investigational anticancer agents for advanced/unresectable HCC (1L) Cohort B 19. Has histopathological documentation of colorectal adenocarcinoma which is advanced (unresectable and metastatic) and not MSI-H or dMMR as documented by a local test report 20. Has received at least 2 prior lines of systemic therapy for unresectable or metastatic disease which includes fluoropyrimidine, irinotecan and oxaliplatin •Participants with known actionable molecular alterations or biomarker for which an approved therapy exists locally a
Exclusion criteria
Exclusion criteria: 1. Is unable to swallow orally administered medication or has a significant GI disorder that may affect study intervention absorption 2. Has a history of a second malignancy that is progressing or has required active treatment within 3 years 3. Has any of the following: • Hypoxia defined as a pulse oximeter reading 480 ms 7. Has a LVEF below the institutional (or local laboratory) normal range as determined by MUGA or ECHO 8. Has urine protein =1 g/24 hours 9. Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain). A participant who is clinically stable after treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible 10. Has preexisting = Grade 3 GI or non-GI fistula 11. Has moderate to severe hepatic impairment (Child-Pugh B or C) 12. Has clinically significant hematuria, hematemesis or hemoptysis (>2.5 mL) of red blood, or other history of significant bleeding within 3 months before screening 13. Has other clinically significant disorders such as: • Serious active nonhealing wound/ulcer/bone fracture • Requirement for hemodialysis or peritoneal dialysis 14. Received colony-stimulating factors or transfusion within 28 days before study treatment initiation 15. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study 16. Has a history of hypersensitivity reaction to any of the investigational agent(s) included in this study Medical Conditions – Cohort A (HCC) Only 17. Has had esophageal or gastric variceal bleeding within the last 6 months 18. Has history of clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to therapy 19. Has clinically apparent ascites on physical examination that is not controlled with medication 20. Has inferior vena cava, or cardiac involvement of HCC based on imaging, verified by BICR 21. Has bleeding or thrombotic disorders or use of factor X inhibitors or anticoagulants requiring therapeutic INR monitoring e.g. warfarin or similar agents. Treatment with low molecular weight heparin is permitted 22. Has medical contraindications that preclude all forms of contrast enhanced imaging (CT or MRI). Prior/Concomitant Therapy 23. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before allocation 24. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to any costimulatory or coinhibitory T-cell receptor either alone or in combination with another agent in any treatment setting 25. Has received prior radiotherapy within 2 weeks of start of study intervention 26. Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug 27. Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study 28. Is currently participating in or has participated in a study of an investigational agent or has used an investig
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR 2. Disease Control Rate (DCR) Per RECIST 1.1 as Assessed by BICR 3. Progression-free Survival (PFS) Per RECIST 1.1 as Assessed by BICR 4. Overall Survival (OS) 5. ORR Per Modified Response Criteria in Solid Tumors Version 1.1 (mRECIST 1.1) for Hepatocellular Carcinoma (HCC) as Assessed by BICR 6. DOR Per mRECIST 1.1 for HCC as Assessed by BICR 7. DCR Per mRECIST 1.1 for HCC as Assessed by BICR 8. PFS Per mRECIST 1.1 for HCC as Assessed by BICR;Timepoint(s) of evaluation of this end point: 1. Up to ~45 months 2. Up to ~45 months 3. Up to ~45 months 4. Up to ~45 months 5. Up to ~45 months 6. Up to ~45 months 7. Up to ~45 months 8. Up to ~45 months | — |
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To assess the safety and tolerability of the combination of pembrolizumab and lenvatinib and belzutifan. 2. To evaluate the confirmed objective response rate (ORR) per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR).;Secondary Objective: 1. To evaluate the duration of response (DOR) per RECIST 1.1 as assessed by BICR. 2. To evaluate disease control rate (DCR) per RECIST 1.1 by BICR. 3. To evaluate the progression-free survival (PFS) per RECIST 1.1 as assessed by BICR. 4. To evaluate the overall survival (OS). 5. To evaluate efficacy outcomes per hepatocellular carcinoma (HCC)-specific modified Response Criteria in Solid Tumors version 1.1 (mRECIST 1.1) (Cohort A) assessed by BICR.;Primary end point(s): 1. Number of Participants Who Experience at Least One Dose-limiting Toxicity (DLT) 2. Number of Participants Who Experience at Least One Adverse Event (AE) 3. Number of Participants Who Discontinue Study Treatment Due to an AE 4. Objective Response Rate Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR);Timepoint(s) of evaluation of this end point: 1. Up to ~21 days 2. Up to ~45 months 3. Up to ~44 months 4. Up to ~45 months | — |
Countries
Australia, Belgium, Brazil, Canada, Chile, France, Germany, Ireland, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Peru, Spain, Turkey, United States
Contacts
Public ContactInvestigación clínica
Merck Sharp & Dohme de España SA
Outcome results
None listed